Onychomycoses are fungal infections of both the fingernails and the toenails accounting for up to 50% of all the nail disorders. They are currently treated by oral and topical administration of the antifungal drugs. Oral antifungal therapy is generally associated with serious adverse effects independent of or associated with a number of significant drug interactions. Topical monotherapy is "less successful" in treating onychomycosis due to poor trans-nail permeation of antifungal drugs. The poor drug absorption across the nail plate could be attributed to reasons such as unfavorable physicochemical properties of the drugs, lack of formulations that can overcome the barrier properties of the nail plate, short residence time of topical formulations and extensive binding of drug to keratin. Topical monotherapy would be successful only when consistent free drug level >MIC is maintained in the nail stratums during the course of treatment. This requires a drug delivery method that can rapidly drive an effective quantity of drug across the nail plate. We propose to develop a novel "Electropulsation" method for the treatment of onychomycosis. We believe that Electropulsation will significantly improve the success rate of topical monotherapy and shorten the duration of treatment of onychomycosis. Electropulsation of the nail plate, in vitro (at 10V/cm2, 50ms pulse duration at 1Hz) delivered an order of magnitude higher amount of drugs (within a 20 minutes treatment period) as opposed to that achieved by conventional topical application (in 24 hours duration). We hypothesize that application of an appropriate Electropulsation protocol can rapidly deliver therapeutically effective quantity of drugs across the nail plate by kinesis of the drug molecules and also by permeabilizing the nail plate as well. In our Aim 1, we propose to study the effect of different Electropulsation protocols on the trans-nail delivery of drugs and to investigate the mechanisms of trans-nail drug transport enhancement. We further hypothesize that the Electropulsation protocols do not cause any significant discomfort in human subjects. In our Aim 2, we propose to assess the tolerability of Electropulsation protocols applied on the nail plate in the healthy human subjects. The completion of these Specific Aims will result in Electropulsation protocols that are effective and safer for clinical applications. PUBLIC HEALTH RELEVANCE: Currently the fungal infection of nails (onychomycosis) is treated with oral and topical antifungal drugs. Oral antifungal therapy is associated with severe side effects and topical monotherapy is less successful due to poor drug penetration into the nail plate. We propose to develop a novel technique;the "Electropulsation" for rapid delivery of drugs across the nail plate, which in turn is likely to significantly improve the success rate of topical monotherapy and shorten the duration of treatment of onychomycosis as well.